T cells are not only key regulators of the immune response to infectious agents but are critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or an enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini. Int. Arch. Allergy Immunol. 104:112-1125, 1994), in the bronchial mucosa of asthmatics (C. J. Corrigan and A. B. Kay. Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland. Crit. Rev. Clin. Lab. Sci. 32:121-182, 1995), in psoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E. Hutchinson. J. Pathol. 174:77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross. Annu. Rev. Physiol. 57:791-804, 1995). An understanding of the mechanisms behind the recruitment and activation of T cells into these tissues may lay the groundwork for novel therapeutic approaches to the treatment of these chronic inflammatory diseases.
T cells, as well as other inflammatory cells, migrate into tissues in response to the production of a variety chemotactic factors. Among these factors are members of a superfamily of 8-12 kDa proteins known as the chemokines (M. Baggiolini, B. Dewald, and B. Moser. Adv. Immunol. 55:97-179, 1994; J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima. Annu. Rev. Immunol. 9:617-648, 199 1). These proteins share common structural feature such as the presence of 3 or 4 conserved cysteine residues (M. Baggiolini, B. Dewald, and B. Moser. Adv. Immunol. 55:97-179, 1994; J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima. Annu. Rev. Immunol. 9:617-648, 199 1). RANTES or Regulated upon Activation Normal T cell Expressed and Secreted is a key member of CC branch of the chemokine family (M. Baggiolini, B. Dewald, and B. Moser. Adv. Immunol. 55:97-179, 1994; J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima. Annu. Rev. Immunol. 9:617-648, 199 1). The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues. The members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser. Adv. Immunol. 55:97-179, 1994; J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima. Annu. Rev. Immunol. 9:617-648, 199 1). Although it is unlikely that a single chemokine mediates solely the recruitment of inflammatory cells into a lesion, RANTES is a key chemokine in the inflammatory reaction of chronic diseases as arthritis and asthma.
RANTES was originally identified as gene product induced late after antigen activation of T-cells (T. J. Schall, J. Jongstra, B. J. Dyer, J. Jorgensen, et al. J. Immunol. 141:1018-1025, 1988). More recently, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L. A. Beck, G. A. Gorgone, D. Proud, et al. J. Immunol. 155:410-418, 1995; O. A. Marfaing-Koka, O. Devergne, G. Gorgone, A. Portier, et al. J. Immunol. 154:18701878, 1994), synovial (P. Rathanaswanai, M. Hachicha, M. M. Sadick, T. J. Schall, et al. J. Biol. Chem. 268:5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bomscheuer, et al. J. Invest. Dermatol. 105:585-591, 1995), mesangial cells (G. Wolf, S. Aberle, F. Thaiss, et al. Kidney Int. 44:795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, A. I. Mallet, E. Christophers, et al. J. Exp. Med. 176:587-592, 1992). In these cells RANTES mRNA is rapidly upregulated in response to IL-1 or TNF.alpha.. Although RANTES mRNA is not usually detected in normal tissues (J. M. Pattison, P. J. Nelson and A. M. Krensky. Clin. Immunother. 4:1-8, 1995), increased mRNA or protein is present in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J. M. Pattison, P. J. Nelson and A. M. Krensky. Clin. Immunother. 4:1-8, 1995; K. C. Nadeau, H. Azuma and N. I. Tilney. Proc. Natl. Acad. USA 92:8729-8733, 1995), in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al. J. Exp. Med. 181:2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J. M. Pattison, P. J. Nelson and A. M. Krensky. Clin. Immunother. 4:1-8, 1995). Increased immunoreactive protein for RANTES is present in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al. Am. J. Resp. Crit. Care Med. 149:A951, 1994) and sputum from asthmatic individuals (C. M. Gelder, P. S. Thomas, D. H. Yates, I. M. Adcock, et al. Thorax 50:1033-1037, 1995).
Samson has recently described a new CC-chemokine receptor called hChem R13 (CC-CKR5). M. Samson, Biochemistry 35, 3362-3367 (1996). We have now demonstrated that RANTES is a ligand for CC-CKR5.